A multipronged approach is used to assess the functional state of the diseased muscle in order to establish possible signs of defect. Membrane characteristics, excitation-contraction coupling, mechanical responses, histochemistry and ultrastructure, and neurotrophic regulatory influences are under examination. Characteristics of muscle atrophy associated with hypersteroidism are being studied along the following lines: (a) intracellular ion concentrations and (b) effects of temperature, dipheylhydantoin and other agents known to influence the rate of the active transport mechanism. We hope to establish whether the cation transport mechanism is, in fact, responsible for the changes in membrane potentials observed in steroid muscle atrophy. In addition, histological, histochemical and electrophysiological suggest that type II fibers (from fast muscles) are primarily affected by chronic steroid administration whereas type I fibers (from slow muscles) are much more resistant. It is conceivable that membrane specificity may account for these differences or that a neurotrophic regulatory mechanism superimposes its influences, resulting in the differential response to steroids. One approach which may permit one to distinguish between these alternatives is the use of measurements which are indicative of the functional loss, if any, of neuronal and/or neurotrophic influences on the muscle. Thus, measurements of frequency and amplitude of the miniature end-plate potentials and measurements of the extent of muscle membrane sensitivity to acetylocholine (Ach) seen in denervation atrophy will be studied to assess possible defects in neurotrophic regulation. We are also examining human normal and diseased intercostal specimens in an attempt to determine which muscle disease entitites are expressed at the muscle level by signs of denervation. Specifically, we are probing and will examine changes in the histochemical profiles of fiber type populations, ultrastructural alterations and functional changes associated with denervation, i.e. appearance of increased Ach sensitivity and tetrodotoxin-resistant membrane excitability.